Multicomponent complex for use with a substrate

ABSTRACT

Compositions and methods for use with substrates which are useful in the sustained delivery of bioeffecting agents are described. The compositions of the invention include a multicomponent complex which attaches a bioeffecting agent to a substrate with an anchor provided by a linker compound which also forms a cleavable linkage so that the bioeffecting agent&#39;s release into the area surrounding the substrate occurs in a sustained manner over an extended period of time. The methods of the invention involve providing a bioeffecting composition on the surface of a substrate so that a bioeffecting agent may be released in a sustained manner over time.

RELATED APPLICATIONS

[0001] This application is a continuation of U.S. application Ser. No.09/501,164, filed Feb. 9, 2000, which is a continuation of U.S.application Ser. No. 09/038,340, filed Mar. 11, 1998, now U.S. Pat. No.6,096,726.

[0002] The entire teachings of the above applications are incorporatedherein by reference.

BACKGROUND OF THE INVENTION

[0003] Bioeffecting agents—agents which engage in a biological activityor are effective in modulating a biological activity—are often appliedto the surface of articles for a variety of purposes. For example, bathmats are often sprayed with agents containing benzalkonium salts toinhibit the growth of microbes. Bioeffecting agents are also used toalter the surface properties of the materials to which they are applied.A pharmaceutical preparation of heparin when applied to a medical deviceprovides its surfaces with antithrombogenic properties.

[0004] To prolong the duration of the bioeffecting activity or to delayits initiation, bioeffecting agents have been encapsulated or embeddedin materials for subsequent release in particular locations or underparticular conditions. For example, polyglycolic and polylactic acidshave found significant usage as resorbable biomaterials and have oftenbeen blended during processing to include a variety of bioeffectingagents. The bioeffecting agents contained in these materials arereleased as the products degrade. The rate of delivery of the agents isdetermined by the local conditions which affect the diffusion of thebioeffecting agents and the degradation of the enclosing materials.Bioeffecting agents have also been incorporated in materials such ashydrogels which swell in moist environments. Hydrogels release theagents through diffusion into the local environment.

[0005] Various types of chemical attachments have been employed to bindbioeffecting agents to articles in attempts to improve the duration ofthe bioeffecting activity. A number of ionic bonds have been used,because bioeffecting agents possessing sufficient ionic charge can bereadily attached to the surfaces of articles containing the oppositeionic charge. Hsu, for example, in U.S. Pat. No. 4,871,357, describes anionic heparin coating for use with medical devices. The release ofmaterials which are attached to substrates with ionic bonds is governedboth by the strength and number of the ionic pairs, and by localconditions such as pH and moisture. Ionic bonds disassociate quiterapidly under moist conditions. Even ionic systems of attachmentdesigned to include protectants against wet environments tend to be lessdurable under those conditions. Ionic attachment can also adverselyaffect the function of bioeffecting materials during the period ofattachment.

[0006] Covalent bonds, relying on a number of functional groups, havebeen used to attach bioeffecting agents to the surface of articles. InU.S. Pat. No. 4,810,784, Larm described a method of covalent attachmentusing glutaraldehyde and aldehyde conversions, while Burns utilized amethod of attachment relying on carbodiimide conversion in U.S. Pat. No.5,527,893. Guire, in U.S. Pat. No. 5,336,579, described a method whichused a combination of isocyanate and photo-activation hydrogenabstraction. While these types of bonds provide good attachment of theagent to the article, they can be difficult and complicated to form onthe surface of the substrate, often requiring multiple modifications. Inaddition, the final covalent bond formed is not generally reversible,and the bioeffecting activity of the agent is often alteredsignificantly by its interaction with the functional group providing theattachment.

SUMMARY OF THE INVENTION

[0007] The present invention is based, at least in part, on thediscovery of a multicomponent complex for reversibly attachingbioeffecting agents to substrates so that the agents may be releasedover an extended period of time while still retaining the capacity forsubstantial bioeffecting activity. The invention provides compositionsand methods for use with substrates which are useful in the sustaineddelivery of bioeffecting agents. The compositions of the inventioninclude a multicomponent complex which attaches a bioeffecting agent toa substrate with an anchor provided by a linker compound which alsoforms a cleavable linkage so that the bioeffecting agent's release intothe area surrounding the substrate occurs in a sustained manner over anextended period of time. The methods of the invention involve providinga bioeffecting composition on the surface of a substrate so that abioeffecting agent may be released in a sustained manner over time.Accordingly, the compositions and methods of the invention are usefulfor delivering bioeffecting agents to a localized area where theirsustained release permits bioeffecting activity to occur over anextended period of time.

[0008] The present invention pertains to a combination of amulticomponent complex for delivering a bioeffecting agent for use witha substrate and an article. The combination includes a complex fordelivering a bioeffecting agent for use with a substrate and fordelivering a bioeffecting agent having a bioeffecting domain component,a segment component containing at least two linking domains, and ananchoring moiety component. Accordingly, the multicomponent complex canhave the formula:

[Q]-[S]-[T]

[0009] where Q is a bioeffecting domain component; S is a segmentcomponent containing at least two linking domains; and T is an anchoringmoiety component; and the components are selected such that a cleavablelinkage anchored to the substrate is formed which sustains the releaseof the bioeffecting agent over time. The combination contains an articlewhich is in contact with the complex. In one preferred embodiment, thearticle is a medical device adapted for in vivo uses.

[0010] The present invention also provides a multicomponent complex fordelivering a bioeffecting agent for use with a substrate having abioeffecting domain component, a segment component containing at leasttwo linking domains, and an anchoring moiety component. Accordingly, themulticomponent complex can have the formula:

[Q]-[S]-[T]

[0011] where Q is a bioeffecting domain component; S is a segmentcomponent containing at least two linking domains; and T is an anchoringmoiety component and the components are selected such that a cleavablelinkage anchored to the substrate is formed which sustains the releaseof the bioeffecting agent over time.

[0012] The present invention also provides a composition for deliveringa bioeffecting agent for use with a substrate. The composition containsa multicomponent complex for delivering a bioeffecting agent for usewith a substrate having a bioeffecting domain component, a segmentcomponent containing at least two linking domains, and an anchoringmoiety component. Accordingly, the multicomponent complex can have theformula:

[Q]-[S]-[T]

[0013] where Q is a bioeffecting domain component; S is a segmentcomponent containing at least two linking domains; and T is an anchoringmoiety component and the components are selected such that a cleavablelinkage anchored to the substrate is formed which sustains the releaseof the bioeffecting agent over time. The composition contains a solutionin contact with the complex.

[0014] The present invention further pertains to packaged compositionsfor delivering a bioeffecting agent for use with a substrate. A packagedcomposition includes a container holding a compound supplying at leastone component of a multicomponent complex for delivering a bioeffectingagent for use with a substrate having a bioeffecting domain component, asegment component containing at least two linking domains, and ananchoring moiety component. Accordingly, the multicomponent complex canhave the formula:

[Q]-[S]-[T]

[0015] where Q is a bioeffecting domain component; S is a segmentcomponent containing at least two linking domains; and T is an anchoringmoiety component and the components are selected such that a cleavablelinkage anchored to the substrate is formed which sustains the releaseof the bioeffecting agent over time. The packaged composition containsinstructions for using the composition to deliver a bioeffectingcompound.

[0016] The present invention also provides methods for providing asustained release bioeffecting coating on the surface of an article byapplying a coating solution to a surface of the article such that alayer containing the sustained release bioeffecting coating is formedupon the article surface, such that the formed layer contains amulticomponent complex containing a bioeffecting domain component, asegment component containing at least two linking domains, and ananchoring moiety component, the components selected such that acleavable linkage anchored to the substrate is formed, and the releaseof the bioeffecting domain is sustained over time.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017]FIG. 1 is an illustration of a one-step method of application of amulticomponent complex of the invention.

[0018]FIG. 2 is an illustration of a two-step method of application of amulticomponent complex of the invention.

[0019]FIG. 3 is an illustration of a three-step method of application ofa multicomponent complex of the invention.

[0020]FIG. 4 is an illustration of a one-step or two-step method ofapplication of a multicomponent complex of the invention.

[0021]FIG. 5 is an illustration of a method of application of amulticomponent complex of the invention including a difunctional spacer.

[0022]FIG. 6 is a graphic representation of the rate of heparin releasefrom a polyurethane film post-coated with a standard benzalkoniumheparin. (3-145-2)

[0023]FIG. 7 is a graphic representation of the rate of heparin releasefrom a polyurethane film created with a solution of aqueous ammoniumheparin. (3-146-7)

[0024]FIG. 8 is a graphic representation of the rate of release ofheparin attached with a multicomponent complex of the invention from apolyurethane film created with a solution of aqueous ammonium heparin.(3-146-4)

[0025]FIG. 9 is a graphic representation of the rate of heparin releasefrom a hydrophilic film of a polyurethane resin. (3-146-9)

[0026]FIG. 10 is a graphic representation of the rate of release ofheparin attached with a mult-component complex of the invention from ahydrophilic polyurethane film. (3-146-5)

DETAILED DESCRIPTION OF THE INVENTION

[0027] The features and other details of the invention will beparticularly described and pointed out in the claims. It will beunderstood that the particular embodiments of the invention are shown byillustration and not as limitations of the invention. The principalfeatures of the invention can be employed in various embodiments withoutdeparting from the scope of the present invention. All parts andpercentages are by weight unless otherwise stated.

[0028] The present invention pertains to compositions and methods usefulin the delivery of bioeffecting agents. The compositions of theinvention include a multicomponent complex which attaches a bioeffectingagent to a substrate with an anchor provided by a linker compound whichalso forms a cleavable linkage with the bioeffecting agent so that thebioeffecting agent's release into the area surrounding the substrateoccurs in a sustained manner over an extended period of time. Thepresent invention also pertains to methods for providing a sustainedrelease bioeffecting coating on the surface of an article by applying acoating solution to a surface of the article.

[0029] The language “multicomponent complex” is intended to include themulticomponent complexes of the invention that attach a bioeffectingagent to a substrate using a cleavable linkage and an anchor. Thecomponents forming the multicomponent complex are selected to form acleavable linkage and an anchor such that the release of thebioeffecting agent is sustained over time. The bioeffecting domaincomponent is supplied by a bioeffecting agent. The segment componentcontaining at least two linking domains is supplied by a linkercompound. The anchoring moiety component is associated with thesubstrate, and may be supplied by the substrate or another compoundplaced in close proximity to the substrate.

[0030] Accordingly, the multicomponent complex of the invention can havethe formula:

[Q]-[S]-[T]

[0031] wherein Q is a bioeffecting domain component; S is a segmentcomponent containing at least two linking domains; and T is an anchoringmoiety component.

[0032] The language “bioeffecting agent” is intended to include amaterial which engages in biological activity or is effective inmodulating a biological activity. A bioeffecting agent may exhibittherapeutic, prophylactic or diagnostic effects in humans, animals,insects and plants. Agents may be proteins, peptides, polysaccharides,enzymes, drugs, vaccines, vitamins, mineral complexes, sunscreens ornutritional supplements. Preferred materials exhibit antithrombogenic,antimicrobial, antihypertensive, anticarcinogenic, anticonvulsive,antiinflammatory, analgesic, antifibrotic, cell growth or cellinhibition, or other properties. Agents may be used to treat a varietyof disease states including Parkinson's Disease, Alzheimer's Disease,and any form of diabetes. Preferred materials include ferrochrome A,erythropoietin, growth hormone, insulin, vitamin C, aspirin and heparin.Particularly preferred materials are anticoagulant compounds andproteins which affect cell growth in humans. A most particularlypreferred compound is ammonium heparin.

[0033] Bioeffecting agents useful in the multicomponent complex of theinvention are those that contain at least one localized site useful as abioeffecting domain component. The site may either be naturallycontained in the agent, or the agent may be modified to contain thesite. Materials modified before, during or after their use in themulticomponent complex of the invention are included in the languagebioeffecting agents as long as they maintain a substantial capacity toengage in biological activity or maintain a substantial effectiveness inmodulating a biological activity. The language “a substantial capacityto engage in biological activity” or “a substantial effectiveness inmodulating a biological activity” is considered to be activity that isat least about 10% of the activity of the unmodified agent, preferablyat least about 20% of the activity of the unmodified agent, mostpreferably at least about 30% of the activity of the unmodified agent.Materials which, as modified, fail to maintain a substantial capacity toengage in biological activity or to maintain a substantial effectivenessin modulating a biological activity, may be subsequently modified toregain a substantial capacity to engage in biological activity or regaina substantial effectiveness in modulating a biological activity e.g., anagent which fails to maintain a substantial capacity to engage inbiological activity when attached to a substrate with a multicomponentcomplex of the invention, but regains a sustantial capacity to engage inbiological activity when released from the multicomponent complex isintended to be included in the language, bioeffecting agent.

[0034] The language “bioeffecting domain component” is intended toinclude a localized site located on a bioeffecting agent. The language“supplied by” is intended to include the use of a bioeffecting domaincomponent contained on a bioeffecting agent in a multicomponent complexof the invention. The bioeffecting domain component is considered to besupplied by the bioeffecting agent on which it is contained. Thebioeffecting domain component is capable of forming a cleavable linkagewhen combined with a linking domain contained in a linker compound. Asite which forms an appropriate covalent chemical bond may be utilized.Preferred sites are acid functional sites containing a carboxylic acid(COOH).

[0035] Bioeffecting agents may naturally contain a bioeffecting domaincomponent. A preferred bioeffecting agent with a naturally occurringbioeffecting domain component is ammonium heparin. Bioeffecting agentsmay be modified to contain a bioeffecting domain component by chemicallyreacting the bioeffecting agent with an appropriate carboxylic acidreactive species. A carboxy modified isocyanate is one example of anappropriate carboxylic acid reactive species, which use is described inExample 8.

[0036] Table 1 below contains a non-limiting list of examples ofbioeffecting agents and a corresponding bioeffective domain componentthey may contain. The table also contains the names of commercialdistributors of bioeffecting agents. TABLE 1 COMPOUNDS, DISTRIBUTORS ANDDOMAINS OF BIOEFFECTING AGENTS Name Supplier(s) Domain AntithrombogenicProperties: Heparin Various —COOH Dermatan sulfate Various Cell GrowthProperties: Ferrochrome A —COOH Erythropoetins —COOH Diethylstilbestrol—OH Lupron —NH2/—OH Estrogen estradiol —OH Androgen halotestinPharmacia/Upjohn —OH Anticarcinogenic Properties: 6-thioguanine GlaxoWellcom —COOH 6-mercaptopurine Glaxo Wellcome —COOH Zolodex —NH2/—OHTaxol —OH Antihypertensive Properties: Lisinopril/Zestril Zeneca COOHStreptokinase COOH Aminobutyric acid OH Hemostatic aminocaproic acidCOOH Parkinson Treatment: Parlodel Sandoz OH Alzheimer's Treatment:Tacrine Hcl ParkeDavis NH2 Antifibrosis: Potaba Glenwood NH2Pharmaceuticals Appetite Control Properties: Adipex Gate Pharmaceuticals—NH2 Anticonvulsive Properties: Memboral Sanofi-Winthrop —COOHPhenobarbital Various —2ON Diabetes Mellitus Treatment: Insulin Various—COOH/NH2 Proteins: Gamma globulin —COOH/NH2 Azathioprine Enzymes:Papein —COOH/NH2 Antiinflammatory/Analgesic Properties: AcetaminophenVarious —OH/2ON Ibuprofen Various —COOH Acetylsalicylic acid derivativesSalflex-Carnick Labs —COOH Epinephrine Various —OH HydrocortisoneVarious —OH Oxycodone Percoset Dupont —OH Dalgan Astra —OH Phrenilinebutabital Carnick Labs —2ON Procaine (topical) —NH2 NovocainSonofi-Winthrop Vitamin/Mineral complexes: Hemin —COOH Vitamin B-12—COOH Folic acid —COOH Magnesium gluconate —COOH Vitamin D —OH Vitamin C—COOH Vitamin E —OH Vitamin A —OH Vitamin U Vitamin L —NH2 Vitamin K—OH/NH2 Panthothenic acid —COOH Ultraviolet Light Inhibitors:Para-aminobenzoicacid —COOH Rodenticides: Aminopterin —NH2 MuscleRelaxant Properties: Aminophenylbutyric acid —COOH Vaccines/VaccineAdjuvants: Hepatitis —COOH/NH2 Chicken pox —COOH/NH2 Measles —COOH/NH2Diptheria —COOH/NH2 Antithemophilic —COOH/NH2 Bayer's Koate —COOH/NH2Antimicrobial Properties: Penicillin Various —COOH Acyclovir GlaxoWellcome —COOH/NH2 Oflaxacin McNeil —COOH Amoxicillin —COOH Tobramycin—NH2 Retrovior —NH2 Epivir —2ON Nevirapine Roxane Gentamycin ScheringPlough —NH2 Duracef —COOH Ablecet Eli Lilly COOH

[0037] The language “substrate” is intended to include a material whichcan be used with the multicomponent complex. Substrates useful with theinvention are those associated with an anchoring moiety component. Thelanguage “associated with an anchoring moiety component” is intended toinclude substrates which naturally contain at least one anchoring moietycomponent, substrates which may be modified to contain at least oneanchoring moiety component, and substates to which materials may beapplied which contain at least one anchoring moiety component. Usefulsubstrates include a variety of solid, semi-solid and gelled materials.Preferred substrates include metals and polymers. Particularly preferredsubstrates are steel and urethane.

[0038] In certain embodiments of the invention, the substrate is notformed into an article. For example, the components of themulticomponent complex of the invention can be added to a bulk materialbefore it is formed into an article. However, in certain embodiments ofthe invention, particularly those in which a substrate is used todeliver a bioeffecting agent in vivo in humans or animals, the substrateis formed into an article. These articles will often be medical devices.The language “medical device” is intended to include an articleregulated under the United States Federal Food, Drug and Cosmetic Act asa medical device.

[0039] Preferred medical devices include catheters, stents and a varietyof medical implants intended for use in humans. These articles vary insize and shape but are at least about a few tenths of a millimeter longand weigh at least about a few milligrams. Such articles are formed of avariety of substrates. Preferred substrates for these embodiments aremetals and polymers. Particularly preferred embodiments are steel andurethanes.

[0040] The language “cleavable linkage” is intended to include thosecovalent chemical bonds which attach bioeffecting agents to substratesin a manner such that when disassociation occurs, and the bioeffectingmaterials are released, the bioeffecting activity of the bioeffectingmaterials is substantially maintained. Covalent bonds which aredisassociated by hydrolyis reactions are preferred. Covalent bonds whichresult in the formation of esters are particularly preferred.

[0041] The language “reversibly attached” is intended to include themanner in which a bioeffecting agent is attached to a substrate with a“cleavable linkage” of the invention.

[0042] The language “supplied by” is intended to include the use of alinking domain contained on a segment component of a linker compound ina multicomponent complex of the invention. The language “segmentcomponent” is intended to include a portion of a linker compound whichcontains a linking domain. A segment component is considered to besupplied by a linker compound. A linking domain is also considered to besupplied by a linker compound.

[0043] The language “linking domain” is intended to include a localizedsite on a segment component of a linker compound which when combinedwith a bioeffecting domain component forms a cleavable linkage. A sitewhich forms an appropriate covalent chemical bond may be utilized.Preferred sites are acid reactive sites containing carboxylic acids.Particularly preferred sites are acid reactive sites containingun-neutralized or fugitive counter-ion carboxylic acids.

[0044] The language “linking domain” is also intended to include alocalized site on a segment component of a linker compound which whencombined with an anchoring moiety component forms an anchor.

[0045] Table 2 below contains a non-limiting list of compounds which cansupply linking domains. The table also contains the names of commercialdistributors of linker compounds. TABLE 2 COMPOUNDS AND DISTRIBUTORS OFLINKING AGENTS Name Supplier(s) aziridine (polyfunctional) Variousincluding: Stahl Chemical, Peabody, MA epoxies (polyfunctional) Variousincluding: epoxy function silanes Dow Chemical, Midland, MI OSISpecialty Chemical, Danbury, CT Shell Chemical, Houston, TX Henkel Corp.Dupont, Wilmington, DE titanate Dupont, Wilmington, DE zirconate Kenrichzircoaluminate Chartwell formaldehyde (derivatives) Cytec, NJUreaformaldehyde condensates Solutia, St. Louis, MO Melamineformaldehyde condensates Glycouril Benzoguanamine

[0046] The language “anchoring moiety component” is intended to includea localized site capable of reacting with a linking domain to form ananchor. The language “anchor” is intended to include a chemical bondthat attaches the segment component to the substrate or to a materialapplied to the substrate. An anchor may be an ionic or a covalentchemical bond. Preferred chemical bonds include urethane, urea, amide,ether, ester, siloxy, alkyl, metal esters, and melamine bonds. Thelanguage “supplied by” is intended to include the use of a linkingdomain contained on a segment component in a multicomponent complex ofthe invention. The anchoring moiety component is considered to besupplied by the substrate or a material applied to the substrate.

[0047] An anchoring moiety may be a naturally occurring site located ona substrate used with the multicomponent complex. Alternately, asubstrate used with a multicomponent complex of the invention may bemodified to contain an anchoring moiety. A substrate may be modified tocontain an anchoring moiety by a method known in the art. Examples ofmethods known in the art include flame treatment, plasma treatment,treatment with ultraviolet or high energy radiation, acid treatment,corona discharge, gas plasma, treatment with various primers, andcopolymerization with functional monomers.

[0048] Alternately, an anchoring moiety may be contained in a materialapplied to a surface of a substrate used with a multicomponent complexof the invention. The material supplying the anchoring moiety may beapplied to the surface of the substrate in a solution separate from asolution containing the multicomponent complex. Alternately, thematerial supplying the anchoring moiety may be mixed with a solutioncontaining the multicomponent complex.

[0049] Table 3 below contains a non-limiting list of materials which cansupply anchoring moieties. The table also contains the names ofcommercial distributors of the materials. TABLE 3 COMPOUNDS ANDSUPPLIERS OF MATERIALS PROVIDING ANCHORING DOMAINS Name/Type Supplier(s)acrylic (emulsion polymers Various including: containing some AA or MAA)Zeneca Resins, Wilmington, MA Stahl Chemical, Peabody, MA B F Goodrich,Leominster MA and Cleveland, OH Rohm and Haas, Philadelphia, PA urethaneVarious including: Zeneca Resins, Wilmington, MA Stahl Chemical,Peabody, MA B F Goodrich, Leominster, MA and Cleveland, OH BayerCorporation, Pittsburgh, PA alkyd CCP Polymers, Kansas City, MO acrylicreactants CCP Polymers, Kansas City, MO polyesters Eastman Chemical,Kingport, TN Akzo Nobel Resins, Lousiville, CT vinyl Union CarbideCorporation, Danbury, CT silicones Tego Chemical, Hopewell, VA GeneralElectric, Waterford, NY nylon Elf Atochem, Philadelphia, PA epoxy ShellChemical, Houston, Tx Ciba Henkel Corporation synthetic rubbers (block BF Goodrich, Cleveland, OH copolymers) Dow Chemical, Midland, MI AirProducts, Allentown, PA acrylic acid polymers Carbopol maleic anhydridepolymers B F Goodrich, Cleveland OH

[0050] The language “sustained release” is intended to include therelease of a bioeffecting agent in a manner such that its appearance ina local environment is delayed and/or prolonged and its bioeffectingactivity is therefore sustained in duration. Sustained release ismeasured by comparing the release of a bioeffecting agent attached to asubstrate with the multicomponent complex of the present invention tothe release of the bioeffecting agent attached to the same substrate byanother means. Any measurable increase is considered to be a sustainedrelease. At least about a two-fold increase is preferred. At least abouta three-fold increase is particularly preferred. The duration of thesustained release will vary from time to time and depending on theactual conditions of use.

[0051] The release of bioeffecting agents attached to substrates withthe multicomponent complex of the present invention is affected by,among other conditions, the combination of pH, moisture and temperaturein the local environment in which it is used. Therefore, it is possibleto control the amount of agent released into a local area over a periodof time by adapting the manner in which the cleavable linkage attachesthe agent to the substrate in relation to the pH, moisture content andthe temperature in the area in which the substrate is utilized. Thelanguage “controlled release” is intended to include adaptations whichpermit a specific dose of a therapeutic bioeffecting agent to bereleased into a local environment for a specified period of time.

[0052] The language “di-functional spacer” is intended to include anymaterial which is attached to the bioeffecting agent for the purpose oforienting its spatial arrangement in a particular manner. Adi-functional spacer useful in the present invention contains at leastone site which permits its attachment to the cleavable linkage or theanchor, or both sites of the multicomponent complex withoutsignificantly compromising the overall function of the complex. Examplesof compounds useful as di-functional spacers include linear, endfunctional di-acid, acid/amine, acid/hydroxy, and acid/unsaturatedmaterials. A preferred compound is aminocaprylic acid.

[0053] A composition containing the multicomponent complex can includeadditional compounds such as hydrophilic agents, some of which renderthe surface of the substrate slippery when placed in a moistenvironment. Some hydrophilic agents cause swelling which incorporatesthe bioeffecting agent into recesses formed on the surface of thesubstrate. The release of the bioeffecting agents can be furtherenhanced by the addition of hydrophilic agents which increase exposureof sensitive ester linkages to the environment.

[0054] Optionally, hydrophilic coreactants, which may be used in forminga polymer, may be added to the compound supplying the anchoring moiety.Such monomers as HEA, HEMA, VP, AA, NIPA can be added to form acrylicco-polymers. Hydroxy-terminal hydrophilic materials such as polyethyleneoxide can be co-reacted to form esters, amides and urethanes to improvehydrophilicity.

[0055] Another aspect of the present invention includes a method inwhich the multicomponent complex is applied to at least one surface of asubstrate. A solution containing the multicomponent complex may beapplied to the surface of the substrate in a one-step application bydipping the substrate into the solution so that a single layer is formedon the surface of the substrate. The solution may contain additionalingredients such as hydrophilic polymers. Other methods of applying thecoating are known to those skilled in the art and may be used in thisapplication. One-step application methods are illustrated in FIGS. 1 and4. In FIG. 1, #1 represents a surface of the substrate, #2 represents anoptional hydrophilic polymer, #3 represents a cleavable linkage, #4represents an anchor and #5 represents a bioaeffecting agent. In FIG. 4,#1 represents the surface of a substrate, #2 represents an optionalprimer layer, #3 represents an anchoring moiety, #4 represents acleavable linkage and #5 represents a bioeffecting agent.

[0056] Alternately, the multicomponent complex may be applied to thesurface of the substrate in a two-step application. A first primer layercontaining a portion of the components necessary to form themulticomponent complex is applied to the surface of the substrate. Then,a second layer containing the remaining components necessary to form themulticomponent complex are applied over the primer layer. Themulticomponent complex in this application is formed in situ. Either ofthe two solutions may contain additional ingredients such as hydrophilicpolymers. Any method known to those of skill in the art may be used toapply the layers of the solutions to the substrate. Two-step applicationmethods are illustrated in FIGS. 2 and 4. In FIG. 2, #1 represents asurface of the substrate, #2 represents a primer layer, #3 represents acleavable linkage, #4 represents an anchor and #5 represents abioeffecting agent. In FIG. 4, #1 represents a surface of the substrate,#2 represents an optional primer layer, #3 represents an anchoringmoiety, #4 represents a cleavable linkage and #5 represents abioeffecting agent.

[0057] Alternately, the multicomponent complex may be applied to thesurface of the substrate in a three-step application A first primerlayer containing a portion of the components necessary to form themulticomponent complex is applied to the surface of the substrate. Then,a second layer containing additional components necessary to form themulticomponent complex are applied over the primer layer. Finally, athird layer containing the remainder of the components necessary to formthe multicomponent complex is applied over the first two layers. Themulticomponent complex in this application is formed in situ. Any of thethree solutions may contain additional ingredients such as hydrophilicpolymers. Any method known to those of skill in the art may be used toapply the layers of the solutions to the substrate. This three-stepapplication is illustrated in FIG. 3. In FIG. 3, #1 represents thesurface of a substrate, #2 represents a primer layer, #3 represents alinker compound, #4 represents a cleavable linkage and #5 represents abioeffecting agent.

[0058] In any of the applications described above, a di-functionalspacer can be interspersed between the cleavable linkage and the anchor.For example, a first primer layer containing a portion of the componentsof the multicomponent complex is applied to the surface of thesubstrate. Successive layers containing a di-functional spacer and theremainder of the components of the multi-component complex are thenapplied. A method of application including a di-functional spacer isillustrated in FIG. 5. In FIG. 5, #1 represents a surface of thesubstrate, #2 represents an optional primer layer, #3 represents alinker compound, #4 represents a linkage of the di-functional spacer, #5represents a di-functional spacer, #6 represents a cleavable linkage and#7 represents a bioeffecting agent.

[0059] In a preferred embodiment of the method of the present invention,a stainless steel substrate is coated by being dipped into a solutioncontaining the multicomponent complex. The coating layer formed ispreferably about one-tenth mil (0.1 mil) to ten mil (10.0 mil) inthickness, even more preferably three-tenths mil (0.3 mil) to five mil(5.0 ml) in thickness, most preferably about one mil (0.5 mil) to threemil (3.0 mil) in thickness. [Note: One mil equals 0.001 inch or 25.0microns]

[0060] Another aspect of the present invention includes a method inwhich the components necessary for forming the multicomponent complexare added into a substrate. Alternately, a solution containing themulticomponent complex can be added to the substrate.

[0061] In another aspect of the invention, the multicomponent complex iscombined with an article in contact with the complex. The article shouldbe of a shape and formed of a material suitable for its purpose. In someembodiments, the articles are medical devices. Preferred medical devicesinclude catheters, stents and a variety of implants. Such articles areformed of a variety of materials. Preferred materials for theseembodiments are metals and polymers. These articles vary in size andshape but are at least about a few tenths of a millimeter long,preferably at least about 0.1, 0.3, 0.5, 0.7 and 0.9, most preferably atleast about 0.5, are at least about a few tenths of a millimeter indiameter, preferably at least about 0.1, 0.3, 0.5, most preferably atleast about 0.3, and weigh at least about a few milligrams, preferablyat least about 1.0, 3.0 and 5.0, most preferably at least about 3.0milligrams.

[0062] In another aspect of the invention, the individual components ofthe multicomponent complex can be supplied in various configurations.Each compound necessary for forming the multicomponent complex of theinvention, the compound supplying the bioeffecting domain, the compoundsupplying the linking segment component containing at least two domainsand the compound supplying the anchoring moiety, can be provided in acontainer supplying at least one component. The language “supplying”when used to describe the manner in which the multicomponent complex isprovided is intended to include provision of the multicomponent complexwhen the multicomponent complex is prepared and used in the samefacility as well as when the multicomponent complex is prepared for usein separate facilities. The language “container” is intended to includeany vessel or package capable of containing for any purpose or anyperiod of time the multicomponent complex, any component of themulticomponent complex, or any compound or material intended to supply acomponent of the multicomponent complex.

[0063] In another embodiment, the compounds necessary for forming themulticomponent complex of the invention, the compound supplying thebioeffecting domain component, the compound supplying the segmentcomponent containing at least two linking domains and the compoundsupplying the anchoring moiety component, can be provided in a containerholding compounds supplying at least two components.

[0064] In yet another embodiment, the compounds necessary for formingthe multicomponent complex of the invention, the compound supplying thebioeffecting domain component, the compound supplying the segmentcomponent containing at least two linking domains and the compoundsupplying the anchoring moiety component, can be provided in a containerholding compounds supplying at least three components.

[0065] In another aspect of the invention, at least one of the compoundsnecessary for forming the multicomponent complex of the invention, thecompound supplying the bioeffecting domain component, the compoundsupplying the segment component containing at least two linking domainsand the compound supplying the anchoring moiety component, can besupplied in a package which contains instructions for forming themulticomponent complex of the invention.

[0066] In another embodiment of the invention, at least two of thecompounds necessary for forming the multicomponent complex of theinvention, the compound supplying the bioeffecting domain component, thecompound supplying the segment component containing at least two linkingdomains and the compound supplying the anchoring moiety component, canbe supplied in a container which contains instructions for forming themulticomponent complex of the invention.

[0067] In yet another embodiment of the invention, at least three of thecompounds necessary for forming the multicomponent complex of theinvention, the compound supplying the bioeffecting domain component, thecompound supplying the segment component containing at least two linkingdomains and the compound supplying the anchoring moiety component, canbe supplied in a container which contains instructions for forming themulticomponent complex of the invention.

[0068] In another aspect of the invention, the invention may be used inmethods of delivering bioeffecting agents to particular locations. Abioeffecting agent can be attached to a substrate with a multicomponentcomplex of the invention by any of the methods described. The substrateis then placed in the location in which it is desired to deliver thebioeffecting agent. After placement of the substrate delivering thebioeffecting agent, disassociation of the cleavable linkage begins tooccur, and the release of the bioeffecting agent in the area surroundingthe substrate begins to occur. The rate of release will be affected bythe conditions in the local environment, e.g. temperature, moisture andpH.

[0069] When delivering bioeffecting agents in vivo in animals or humansthe substrate is in the form of an article capable of providing adequatesupport and surface area for the delivery of the bioeffecting agent. Thesize and shape of the article will vary depending on the method ofdelivery being used and the desired role of the bioeffecting agent.

[0070] For example, a stent may be coated with compositions containingthe multicomponent complex of the invention. The stent may be placed ona catheter which can be threaded through the human vasculature until adesired location is reached. The stent may be removed from the catheterand may be retained in the desired location for some period of time. Inthe moist environment of the vasculature, hydrolysis reactions willbegin to release the bioeffecting agent into the area surrounding thestent. Bioeffecting agents delivered locally can be very effective intreating a range of disease states and conditions. It is often possibleto obtain the desired effect using a very small amount of thebioeffecting agent, because it is being targeted to the desired area.Local delivery also avoids the systemic effects which often result whenagents are delivered by traditional routes, such as ingestion andinjection. For example, when heparin is delivered to a particular sitein the vasculature, its antithrombogenic and antiproliferative effectscan be realized in a desired location without causing the systemic“blood thinning” caused when heparin is administered by other routes.

[0071] The articles used to deliver bioeffecting agents can take avariety of forms. A polymer can be used to occlude an artery. Abioeffecting agent with antibacterial properties can be absorbed intothe polymer using a multicomponent complex of the invention. Theantibacterial agent will be slowly released and will prevent infectionat the site of occlusion. Delivery of the antibacterial agent in thismanner allows the use of advantageous lower doses of bioeffecting agentsand potentially avoids systemic effects, such as the opportunisticfungal infections which often result from lengthy courses of antibiotictreatment.

[0072] The invention is further illustrated by the followingnon-limiting examples. The contents of all the references citedthroughout this application are expressly incorporated by reference.

EXAMPLE 1 Preparation of a Sustained Release Antimicrobial Coating

[0073] The following components are combined in the order listed:

[0074] 100 parts by weight UE 40-439

[0075]10 parts by weight protargen (silver protein)

[0076] 5 parts by weight KM 10-1610 (leveling/flow aid)

[0077] 5 parts by weight KM 10-1703 (linker)

[0078] (UE 40-439, KM 10-1610, and KM 10-1703 can be purchased fromStahl of Peabody, Mass.)

[0079] After mixing with good agitation, the mixture is allowed to standfor 30 minutes. The mixture can then be applied to the surface of astandard vinyl bath mat until a 3.0 mil thick coating is obtained. Thecoating will inhibit microbial growth, both bacterial and fungal.

EXAMPLE 2 Preparation of a Sustained Release Antimicrobial Resin

[0080] The following components are combined in the order listed:

[0081] 5 parts by weight nystatin (Mycostatin)

[0082] 5 parts by weight protargen (silver protein)

[0083] 5 parts by weight KM 10-1703 (linker)

[0084] * pigment and stabilizers are optional additions

[0085] (KM 10-1703 can be purchased from Stahl of Peabody, Mass. andMycostatin can be purchased from Bristol Myers Squibb)

[0086] After mixing with good agitation, the dry mixture is added to 100parts of a dry blend of vinyl resin containing a small amount of acidfunctional vinyl resin. (A pre-mill of the dry blend of the vinylcomposition may be dictated.) The vinyl resin should be milled accordingto standard roll manufacturing with minimal heat history.

[0087] A flexible vinyl film formulation containing standard weights ofvinyl resin forms. A multicomponent complex of the invention also forms,which attaches the bioeffecting agents containing antimicrobial andantifungal properties to the vinyl resin. The vinyl composite filmformed is useful for items such as bath mats and shower curtains.

EXAMPLE 3 Comparison of the Binding Stability of the Sodium and AmmoniumSalts of Heparin

[0088] Ammonium heparin was purchased from Celsus Labs. Sodium heparinand toluidine blue O were purchased from Aldrich. MichemPrime 4983R waspurchased from Michelman. KM 10-1703 was purchased from Stahl ofPeabody, Mass.

[0089] Two solutions, each containing 2% solids of sodium heparin andammonium heparin in a 50/50 blend of water and isopropanol wereprepared. One glass slide was dipcoated in the solution containingsodium heparin, and another glass slide was dipcoated in the solutioncontaining the ammonium heparin.

[0090] An emulsion of MichemPrime 4983R (acrylic polymer) was diluted toa 50/50 weight ratio and added to the heparin solutions. An excess of KM10-1073 (linker) was also added to each solution. One glass slide wasdipcoated in the solution containing sodium heparin/acrylic, and anotherglass slide was dipcoated in the solution containing the ammoniumheparin/acrylic.

[0091] The binding stability of heparin to the glass substrate wasevaluated by staining in a 2% solution of toluidine blue O, rubbing andrinsing the slides: Stain Sample No. Compound Binding StabilityIntensity 3-176 A Ammonium Heparin removes w/rubs strong 3-176 BAmmoniium persists w/10 rubs faint Heparin/Linker/Binder 3-176 G SodiumHeparin removes w/falling strong water 3-176 F Sodium removes with rubsfaint Heparin/Linker/Binder

[0092] In selecting a heparin additive, sodium heparin salts aregenerally chosen due to the ability of the body to easily handle sodiume.g. isotonic saline is based on sodium chloride. The sodium counter-ionis naturally occurring and biologically a known quantity. However, thesodium salt of heparin, while a bioeffecting agent, does not contain abioeffecting domain component and cannot form a cleavable linkage with alinking domain. The ammonium salt of heparin, however, naturallycontains a bioeffecting domain component. Therefore, this experimentdemonstrated that an ammonium heparin salt attached to a substrate witha multicomponent complex of the invention is released more slowly thaneither sodium heparin or ammonium heparin attached in another manner.

EXAMPLE 4 Assessment of Binding Stability of Ammonium Heparin Salt withVarious Linker Compounds

[0093] Ammonium heparin was purchased from Celsus Labs. Toluidine blue Odye was purchased from Aldrich. KM 10-1703 was purchased from Stahl ofPeabody, Mass. Tyzor AA was purchased from Dupont of Wilmington, Del.Cymer 303 was purchased from Cytec, New Jersey. Epi-rez-5522-WY-55 waspurchased from Shell Chemical, Texas.

[0094] A solution containing 2% solids of ammonium heparin in a 50/50blend of water and isopropanol was prepared. Solutions containingsamples of KM-1703 (linker), Tyzor AA (titanite), and Cymer 303(melamine-formaldehyde), and Epi-rez 5522-WY-55 (epoxy) were added toaliquots of the ammonium heparin solution. One glass slide was dipcoatedin each solution.

[0095] The binding stability of heparin to the glass substrate wasevaluated by staining in 2% solution of toluidine blue O, rubbing andrinsing the slides: Sample No. Compound Binding/Stability StainIntensity 3-176 C ammonium stays w/10 rubs moderate heparin/aziridine3-176 D ammonium removes with rubs strong heparin/titanate morepersistent than 3-176 A 3-176 E ammonium stays w/10 rugs moderateheparin/melamine 3-176 H ammonium removes with rubs moderateheparin/epoxy more persistent than 3-176 A 3-176 A ammonium removes withrubs strong heparin/none 3-176 G sodium removes with strong heparin/nonefalling water

[0096] After being soaked for 24 hours in water, all the samplesmaintained a level of stain color similar to the level of stain colorbefore soaking. The aziridine and the melamine linked complexes appearedto be the most durable of the compounds tested, but all compounds testeddemonstrated an improvement over the control samples.

EXAMPLE 5 Experimental Comparison of the Rate of Release of a ProteinBioeffecting Agent

[0097] Triton X-100 was purchased from Rohm & Hass, Pennsylvania. BSAwas obtained from the Chemistry Department, University of Lowell.MichemPrime 4983R was purchased from Michelman. KM 10-1703 was purchasedfrom Stahl of Peabody, Mass.

[0098] Approximately 1% Triton X-100 (a nonionic surfactant) was addedto a solution of fluorescamine labelled bovine serum albumin (BSA). Anemulsion of MichemPrime 4983R (acrylic polymer) was diluted to 15%solids in water by weight. A solution containing 10% solids in water byweight of KM 10-1703 was also prepared.

[0099] Four glass slides were dipped into the acrylic emulsion, and theexcess emulsion was allowed to drain from the slide for 5 minutes. Theslides were then dried at 150° F. for 15 minutes. Two of the slides weresoaked for 5 minutes in the KM 10-1703 solution. These slides were thendried at ambient temperature for 15 minutes. One drop of the labelledBSA solution was added to each side of all 4 slides. The slides wereallowed to dry at ambient temperature overnight. After drying, theslides were soaked for 15 minutes in water at 37° C. and then examined.

[0100] Under ultraviolet light, the coating on the slides treated withthe KM 10-1703 solution appeared to glow, indicating the continuedpresence of BSA. These slides appeared hazy under normal lightingconditions. The slides not treated with the KM 10-1703 solution showedno changes under either lighting condition, indicating no labeled BSAremained. The appearance of both sets of slides was unchanged after thesecond soaking period.

[0101] The fluorescamine labeling chemical/technique used in thisexample binds the amine functionality on the BSA protein chain, leavingthe acid functions available for reaction. This labeling technique isroutinely used to observe the spectrophotometric/chromatographicseparation of proteins. The results obtained in this experimentdemonstrated that the release of a protein (BSA), attached to asubstrate with a multicomponent complex of the present invention wassustained over time, in comparison to the same protein attached to thesame substrate attached in an alternate manner.

EXAMPLE 6 Rate of Heparin Release from a Substrate (Two-Step ApplicationMethod)

[0102] R-9603 was purchased from Zeneca Resins, Wilmington, Mass.Povidone 90 was purchased from ISP Chemicals, New Jersey. KM 10-1703 waspurchased from Stahl, Peabody, Mass. Ammonium and benzalkonium heparinwere purchased from Celsus Labs. Distilled water was purchased fromPoland Springs, Me.

[0103] A first urethane solution was prepared by dissolving 150.0 gR-9603, 16.8 g PVP and 3.0 g KM 10-1703 in 87.35 g distilled water. Asecond urethane solution was prepared by dissolving 150.0 g R-9603, 16.8g PVP and 4.5 g KM 10-1703 in 87.35 g distilled water. Dried films wereprepared that were approximately 3.0 mils thick. A 2% by weight ammoniumheparin solution was also prepared.

[0104] The three samples were coated as follows:

[0105] 3-145-2 Dried film of first urethane solution; post-dipped inbenzalkonium chloride salt of heparin.

[0106] 3-146-7 Dried film of first urethane solution; post-dipped inammonium heparin solution.

[0107] 3-145-4 Dried film of second urethane solution; post-dipped inammonium heparin solution.

[0108] Coating squares 1.0 cm per side in size were prepared by castingaqueous dispersions of urethane containing a hydrophilic polymer andheparin. After soaking the coating squares for 1 hour in a 0.9% aqueoussaline solution, a sample was taken and the saline solution changed. Inthe same manner, the soaking solutions were removed, and fresh salineadded to containers containing the squares after 12 hours and at 1, 4,5, 6, 7, 10 and 14 days. (The purpose of this flushing was to mimic thecontinual flushing of residual bioeffecting material from the site ofuse by blood, urine or other passing fluids.)

[0109] A pooled human plasma sample was used to obtain partialthromboplastin times (PTT). Various dilutions of the samples were usedto determine the ranges for maximum sensitivity per sample. Measurementswere taken in seconds and times of approximately 70-150 seconds weresought. Back-calculating through the dilutions provided the actuallevels of release.

[0110] As can be seen from the graphs of FIGS. 6-8, the release ofheparin from a coating square one cm in size and approximately 3.0 milsthick occurs as follows:

[0111]FIG. 6—3-145-2 Control/standard coating. Release of therapeuticamounts of heparin; less than 1.0 IU is lost at 0.75 days.

[0112]FIG. 7—3-146-7 Coating without multicomponent complex. Release wasinconsistent; no therapeutic level observed at any time.

[0113]FIG. 8—3-145-4 Coating with multicomponent complex. Release wassignificantly more uniform and prolonged with some activity maintainedat a low level at two weeks. Therapeutic levels were lost at 0.5 dayssimilar to the benzalkonium salt.

[0114] These results demonstrate the improvement in the rate of releasefor heparin attached with a multicomponent complex of the invention,when compared to ammonium heparin without attachment (first urethanesolution).

EXAMPLE 7 Rate of Heparin Release from a Hydrophilic Substrate (One-StepApplication Method)

[0115] R-9603 was purchased from Zeneca Resins, Wilmington, Mass.Povidone 90 was purchases from ISP Chemicals, New Jersey. KM 10-1703 waspurchased from Stahl, Peabody, Mass. Ammonium and benzalkonium heparinwere purchased from Celsus Labs. Distilled water was purchased fromPoland Springs, Me.

[0116] As in Example 6, the first urethane solution was prepared bydissolving 150.0 g R-9603, 16.8 g PVP and 3.0 g KM 10-1703 in 87.35 gdistilled water. Dried films were prepared that were approximately 3.0mils thick.

[0117] 3-145-2 Dried film of first urethane solution; post-dipped inbenzalkonium chloride salt of heparin.

[0118] A second urethane solution was prepared by dissolving 150.0 gR-9603 and 16.8 g PVP in 87.35 g distilled water. 10% by weight ammoniumheparin was added to the solution and allowed to dissolve.

[0119] A third urethane solution was prepared by dissolving 150.0 gR-9603, 16.8 g PVP and 4.5 g KM 10-1703 in 87.35 g distilled water. 10%by weight ammonium heparin was added to the solution and allowed todissolve.

[0120] Dried films of the second urethane solution (3-146-9) and thethird urethane solution (3-146-5) were prepared that were approximately3.0 mils thick.

[0121] Coating squares 1.0 cm per side in size were prepared by castingaqueous dispersions of urethane containing a hydrophilic polymer andheparin. After soaking the coating squares for 1 hour in a 0.9% aqueoussaline solution, a sample was taken and the saline solution changed. Inthe same manner, the soaking solutions were removed, and fresh salineadded to containers containing the squares after 12 hours and at 1, 4,5, 6, 7, 10 and 14 days. (The purpose of this flushing was to mimic thecontinual flushing of residual bioeffecting material from the site ofuse by blood, urine or other passing fluid.)

[0122] A pooled human plasma sample was used to obtain partialthromboplastin times (PTT). Various dilutions of the samples were usedto determine the ranges for maximum sensitivity per sample. Measurementswere taken in seconds and times of approximately 70-150 seconds weresought. Back-calculating through the dilutions provided the actuallevels of release.

[0123] (By way of reference, experience indicates that day five afterstenting appears to be the worst for thrombosis. Therefore, the criticalrelease of an anticoagulant in the vicinity of a stent should bemeasurable (i.e. above a rate of 1.0 IU/24 hour) for the four (4)preceding days. After that there is initial indication that theprolonged release of heparin and/or other bioeffecting cell growthregulators can impact the proliferative response to reduce thereclosure, restenosis and/or damage to the surrounding cells which oftenfollows arterial trauma.)

[0124] As can be seen from the graphs of FIGS. 6, 9 & 10, the release ofheparin from a coating square one cm in size and approximately 3.0 milsthick occurs as follows:

[0125]FIG. 6—3-145-2 Control/standard coating. Release of therapeuticamounts of heparin; less than 1.0 IU is lost at 0.75 days.

[0126]FIG. 9—3-146-9 Hydrophilic coating without multicomponent complex.Showed initially strong release above 1.0 IU/24 hr. Therapeutic levelslost at day 1. Some lower and declining activity was maintained atmeasurable levels through day 14.

[0127]FIG. 10—3-146-5 Hydrophilic coating with multicomponent complex.Therapeutic levels maintained throughout the test. A fairly straightline level amount was released at 1.0 IU for the period between 1-14days. Only slight loss in activity over 14 days.

[0128] These results additionally demonstrate the improvement insustained release for the heparin sample attached to the substrate witha multicomponent complex of the invention.

EXAMPLE 8 Modification of a Bioeffecting Agent

[0129] A reaction product of aliphatic isophorone diisocyanate (IPDI)with dimethylolpropionic acid (DMPA) is prepared by reaction undernitrogen purge at 100° C. for 4 hours, of 2 equivalents of isocyanategroups from IPDI with 1 equivalent of DMPA hydroxyl groups. Due to thedifferential reactivity of the isocyanate groups on IPDI, there is largeamount of isocyanate-“capped” DMPA. A titration of the isocyanatefunctionality yields the % available NCO for reaction with the aminefunction on silver sulfadiazine (SSD). The isocyanate functional productis then added to 2 equivalents (calculated from the % isocyanate of thetitration by standard backtitration of dibutyl amine with hydrochloricacid) of amine functional silver sulfadiazine and the amine/NCO reactionshould proceed rapidly with some exotherm.

[0130] The resulting acid functional derivative of SSD is neutralizedwith ammonia and used in preparation of a coating product as in Examples6 or 7. A coating prepared in this manner would exhibit prolongedantimicrobial activity.

EXAMPLE 9 Difunctional Spacer

[0131] A polymer surface is primed with a solution of acid containingpolymer (MichemPrime 4983R, Michelman) and allowed to dry. The surfaceis washed with a ten percent (10%) aqueous solution of Waterpoxy 1401(Henkel Corporation) polyfunctional epoxy and baked thirty (30) minutesat 150° C. to dry. Within four hours, the samples are immersed in a C-8terminal-acid/amine functional 8-aminocaprylic acid solution and allowedto remain for 15 minutes. The sample is removed and dried 30 minutes at100° C. After rinsing in running water to remove any unreacted caprylicacid, the sample is immersed in a pre-mixed, aged solution of thereaction product of 3 imine equivalents of KM 10-1703 reacted with 1equivalent of acid function of nystatin (Mycostatin Bristol, Myers,Squibb). The resulting layered structure allows more availability of thenystatin to its environment and an increased exposure to the hydrolyticdegradation in that environment.

EXAMPLE 10 Arterial Occluder with Reversibly Attached BioeffectingAgents

[0132] Using the method described below, an artery which provides ablood supply to a tumor can be injected with a swellable polyvinylalcohol (PVA) in its dried, flake form. The PVA quickly expands andoccludes the lumen of the artery. PVA flakes (Cook, Inc., Bloomington,Ind.) are expanded into a solution of aqueous multicomponent complexwhich is isocyanate functional. PVA contains a reactive-OH (hydroxyl)group.

[0133] A reactive pre-polymer (Desmodur N-100, Bayer Corp., Pittsburgh,Pa.) is pre-reacted with a 0.5 stoichiometric (consuming 0.5 equivalentsof the NCO groups with the OH groups) amount of dimethylolpropionic acid(DMPA). All the acid functionality on the DMPA is reacted (1.0equivalents) with three times (3.0 equivalents) of a linking agent (KM10-1703, Stahl, Peabody, Mass.). A growth regulator e.g. Ferrochrome A,and chemotherapeutic agents e.g. 6-thioguanine (Glaxo Wellcome) can beattached to the resulting linking domains in the desired ratio, with astoichiometric amount of acid groups on the bioactive agent for theavailable linking domains.

[0134] The above reaction product exhibits an isocyanate functionality,which can be verified by IR and quantified by standard dibutylamine/hydrochloric acid back titration of isocyanates. It is thendispersed into water at approximately 10% solids or less. If necessarysurfactants and cosolvents can be added to improve the dispersibility orptake by the PVA flakes.

[0135] Finally, the PVA flake is added and swollen in the aqueousmixture, cured at 70° C. overnight and vacuum dried. The subsequentproduct shows good activity of the bioeffecting agent, with littleeffect on the function of the flakes.

[0136] Those skilled in the art will recognize, or be able to ascertainusing no more than routine experimentation, numerous equivalents to thespecific embodiments described herein. Such equivalents are consideredto be within the scope of this invention and are covered by thefollowing claims.

What is claimed is:
 1. The combination of a multicomponent complex fordelivering a bioeffecting agent for use with a substrate and an article,comprising a first complex for use with a substrate and for delivering abioeffecting agent having the following formula: [Q]-[S]-[T]wherein Q isa bioeffecting domain component; S is a segment component containing atleast two linking domains; and T is an anchoring moiety component, thecomponents selected such that a cleavable linkage anchored to thesubstrate is formed which sustains the release of the bioeffecting agentover time, and a second article in contact with the first complex. 2.The combination of claim 1 wherein the bioeffecting domain component issupplied by a compound which has a property selected from the groupconsisting of agents with antithrombogenic, antimicrobial,antiinflammatory, analgesic, and cell growth properties.
 3. Thecombination of claim 2 wherein the agent is a heparin compound.
 4. Thecombination of claim 3 wherein the heparin compound is ammonium heparin.5. The combination of claim 1 wherein the bioeffecting domain componentis supplied by a compound selected from the group consisting ofvitamins, mineral complexes, proteins and enzymes.
 6. The combination ofclaim 5 wherein the bioeffecting domain component is supplied by acompound which is a cell growth factor.
 7. The combination of claim 1wherein the cleavable linkage is an ester.
 8. The combination of claim 1wherein the segment component is supplied by a compound selected fromthe group consisting of aziridines, epoxys, formaldehydes and metalesters.
 9. The combination of claim 8 wherein the segment component issupplied by an aziridine.
 10. The combination of claim 1 wherein thearticle is a medical device.
 11. The combination of claim 10 wherein themedical device is adapted for in vivo uses.
 12. A multicomponent complexfor delivering a bioeffecting agent for use with a substrate having thefollowing formula: [Q]-[S]-[T]wherein Q is a bioeffecting domaincomponent; S is a segment component containing at least two linkingdomains; and T is an anchoring moiety component, the components selectedsuch that a cleavable linkage anchored to the substrate is formed whichsustains the release of the bioeffecting agent over time.
 13. Thecomplex of claim 12 wherein the bioeffecting domain component issupplied by a compound with a property selected from the groupconsisting of agents with antithrombogenic, antimicrobial,antiinflammatory, analgesic, and cell growth properties.
 14. The complexof claim 13 wherein the agent is a heparin compound.
 15. The complex ofclaim 14 wherein the heparin compound is ammonium heparin.
 16. Thecomplex of claim 12 wherein the bioeffecting domain component issupplied by a compound selected from the group consisting of vitamins,mineral complexes, proteins and enzymes.
 17. The complex of claim 16wherein the bioeffecting domain component is supplied by a growthfactor.
 18. The complex of claim 12 wherein the cleavable linkage is anester.
 19. The complex of claim 12 wherein the segment component issupplied by a compound selected from the group consisting of aziridines,epoxys, formaldehydes and metal esters.
 20. The complex of claim 19wherein the segment component is supplied by an aziridine.
 21. Thecomplex of claim 12 wherein the anchoring moiety component is suppliedby a urethane.
 22. The complex of claim 12 wherein the substrate is amedical device.
 23. The complex of claim 22 wherein the medical deviceis adapted for in vivo uses.
 24. A composition for delivering abioeffecting agent for use with a substrate comprising: a first complexfor use with a substrate and for delivering a bioeffecting agent havingthe following formula: [Q]-[S]-[T] wherein Q is a bioeffecting domaincomponent; S is a segment component containing at least two linkingdomains; and T is an anchoring moiety component, the components selectedsuch that a cleavable linkage anchored to the substrate is formed whichsustains the release of the bioeffecting agent over time, and a secondsolution in contact with the first complex.
 25. The composition of claim24 wherein the compounds supplying Q, S and T are provided in acontainer as a single component.
 26. The composition of claim 24 whereinthe compounds supplying Q, S and T are provided as two components. 27.The composition of claim 24 wherein the compounds supplying Q, S and Tare provided as three components.
 28. The composition of any of claims25, 26 or 27 wherein Q is supplied by a compound with a propertyselected from the group consisting of pharmaceuticals withantithrombogenic, antimicrobial, antiinflammatory, analgesic, and cellgrowth properties.
 29. The composition of claim 28 wherein thepharmaceutical is a heparin compound.
 30. The composition of claim 29wherein the heparin compound is ammonium heparin.
 31. The composition ofany of claims 25, 26 or 27 wherein Q is supplied by a compound selectedfrom the group consisting of vitamins, mineral complexes, proteins andenzymes.
 32. The composition of claim 31 wherein Q is supplied by agrowth factor.
 33. The composition of any of claims 25, 26 or 27 furthercomprising a hydrophilic agent.
 34. The composition of any of claims 25,26 or 27 wherein the cleavable linkage is an ester.
 35. The compositionof any of claims 25, 26 or 27 wherein S is supplied by a compoundselected from the group consisting of aziridines, epoxys, formaldehydesand metal esters.
 36. The composition of claim 35 wherein S is suppliedby an aziridine.
 37. The composition of any of claims 25, 26 or 27wherein the anchoring moiety component is supplied by a urethane. 38.The complex of any of claims 25, 26 or 27 wherein the substrate is amedical device.
 39. The complex of claim 38 wherein the medical deviceis adapted for in vivo uses.
 40. A packaged composition for delivering abioeffecting agent for use with a substrate comprising: a containerholding a compound supplying at least one component of a multicomponentcomplex having the following formula: [Q]-[S]-[T] wherein Q is abioeffecting domain component; S is a segment component containing atleast two linking domains; and T is an anchoring moiety component, thecomponents selected such that a cleavable linkage anchored to thesubstrate is formed which sustains the release of the bioeffecting agentover time, and instructions for using the composition for delivering abioeffecting agent.
 41. The packaged composition of claim 40 wherein thecompound supplying Q is contained in the package.
 42. The packagedcomposition of claim 40 wherein the compound supplying S is contained inthe package.
 43. The packaged composition of claim 40 wherein thecompound supplying T is contained in the package.
 44. The packagedcomposition of claim 40 wherein the bioeffecting domain component issupplied by a compound with a property selected from the groupconsisting of agents with antithrombogenic, antimicrobial,antiinflammatory, analgesic, and cell growth properties.
 45. Thepackaged composition of claim 44 wherein the agent is a heparincompound.
 46. The packaged composition of claim 45 wherein the heparincompound is ammonium heparin.
 47. The packaged composition of claim 40wherein the bioeffecting domain component is supplied by a compoundselected from the group consisting of vitamins, mineral complexes,proteins and enzymes.
 48. The packaged composition of claim 40 whereinthe bioeffecting domain component is supplied by a growth factor. 49.The packaged composition of claim 40 wherein the cleavable linkage is anester.
 50. The packaged composition of claim 40 wherein the segmentcomponent is supplied by a compound selected from the group consistingof aziridines, epoxys, formaldehydes and metal esters.
 51. The packagedcomposition of claim 40 wherein the segment component is supplied by anaziridine.
 52. The packaged composition of claim 40 wherein theanchoring moiety component is supplied by a urethane.
 53. The packagedcomposition of claim 40 wherein the substrate is a medical device. 54.The packaged composition of claim 53 wherein the medical device isadapted for in vivo uses.
 55. A method for providing a sustained releasebioeffecting coating on the surface of an article, the methodcomprising: applying a coating solution to a surface of the article suchthat a layer containing the sustained release bioeffecting coating isformed upon the article surface, wherein the formed layer contains amulticomponent complex containing a bioeffecting domain component, asegment component containing at least two linking domains, and ananchoring moiety component, the components selected such that acleavable linkage anchored to the substrate is formed, and the releaseof the bioeffecting domain is sustained over time.
 56. The method ofclaim 55 wherein the bioeffecting domain component is supplied by acompound with a property selected from the group consisting of agentswith antithrombogenic, antimicrobial, antiinflammatory, analgesic, andcell growth properties.
 57. The method of claim 56 wherein the agent isa heparin compound.
 58. The method of claim 57 wherein the heparincompound is ammonium heparin.
 59. The method of claim 55 wherein thebioeffecting domain component is supplied by a compound selected fromthe group consisting of vitamins, mineral complexes, proteins andenzymes.
 60. The method of claim 59 wherein the bioeffecting domaincomponent is supplied by a growth factor.
 61. The method of claim 55wherein the coating solution contains a hydrophilic agent.
 62. Themethod of claim 55 wherein the cleavable linkage is an ester.
 63. Themethod of claim 55 wherein the segment component is supplied by acompound selected from the group consisting of aziridines, epoxys,formaldehydes and metal esters.
 64. The method of claim 63 wherein thesegment component is supplied by an aziridine.
 65. The method of claim55 wherein the article is a medical device.
 66. The method of claim 55wherein the medical device is adapted for in vivo uses.